tbuckley/cabot-search huggingface dataset:
Chimeric Antigen Receptor T-cell Therapy in Hematologic Malignancies and Patient-reported Outcomes: A Scoping Review
Authors: Fabio Efficace, Laura Cannella, Francesco Sparano, Johannes M. Giesinger, Marco Vignetti, Frédéric Baron, Eduardo Bruera, Mario Luppi, Uwe Platzbecker
Journal: HemaSphere (2022)

The inclusion of patient-reported outcome (PRO) measures in chimeric antigen receptor (CAR) T-cell therapy research is critical for understanding the impact of this novel approach from a unique patient standpoint. We performed a scoping review to map the available literature on the use of PRO measures in CAR T-cell therapy studies of patients with hematologic malignancies published between January 2015 and July 2022. Fourteen studies were identified, of which 7 (50%) were investigational early-phase trials, 6 (42.9%) were observational studies, and 1 (7.1%) was a pilot study. The EQ-5D and the PROMIS-29 were the 2 most frequently used PRO measures, being included in 6 (42.9%) and 5 (35.7%) studies, respectively. Despite differences in study designs, there seems to be evidence of improvements over time since CAR T-cell infusion in important domains such as physical functioning and fatigue, at least in patients who respond to therapy. Overall, the studies identified in our review have shown the added value of PRO assessment in CAR T-cell therapy research by providing novel information that complements the knowledge on safety and efficacy. However, there are several questions which remain to be answered in future research. For example, limited evidence exists regarding patient experience during important phases of the disease trajectory as only 4 (28.6%) and 5 (35.7%) studies provided information on PROs during the first 2 weeks from CAR T-cell infusion and after the first year, respectively. Time is ripe for a more systematic implementation of high-quality PRO assessment in future clinical trials and in real-life settings of patients treated with CAR T-cell therapy.
Natural course of health and well-being in non-hospitalised children and young people after testing for SARS-CoV-2: a prospective follow-up study over 12 months
Authors: Snehal M. Pinto Pereira, Roz Shafran, Manjula D. Nugawela, Laura Panagi, Dougal Hargreaves, Shamez N. Ladhani, Sophie D. Bennett, Trudie Chalder, Emma Dalrymple, Tamsin Ford, Isobel Heyman, Kelsey McOwat, Natalia K. Rojas, Kishan Sharma, Ruth Simmons, Simon R. White, Terence Stephenson
Journal: The Lancet Regional Health - Europe (2022)

Despite high numbers of children and young people (CYP) having acute COVID, there has been no prospective follow-up of CYP to establish the pattern of health and well-being over a year following infection.
Intracellular chloride regulation mediates local sleep pressure in the cortex
Authors: Hannah Alfonsa, Richard J. Burman, Paul J. N. Brodersen, Sarah E. Newey, Kashif Mahfooz, Tomoko Yamagata, Marios C. Panayi, David M. Bannerman, Vladyslav V. Vyazovskiy, Colin J. Akerman
Journal: Nature Neuroscience (2022)
CSN6 Mediates Nucleotide Metabolism to Promote Tumor Development and Chemoresistance in Colorectal Cancer
Authors: Shaomin Zou, Baifu Qin, Ziqing Yang, Wencong Wang, Jieping Zhang, Yijing Zhang, Manqi Meng, Junyan Feng, Yunling Xie, Ling Fang, Lishi Xiao, Peng Zhang, Xiangqi Meng, Hyun Ho Choi, Weijie Wen, Qihao Pan, Bart Ghesquière, Ping Lan, Mong-Hong Lee, Lekun Fang
Journal: Cancer Research (2022)

Abstract Metabolic reprogramming can contribute to colorectal cancer progression and therapy resistance. Identification of key regulators of colorectal cancer metabolism could provide new approaches to improve treatment and reduce recurrence. Here, we demonstrate a critical role for the COP9 signalosome subunit CSN6 in rewiring nucleotide metabolism in colorectal cancer. Transcriptomic analysis of colorectal cancer patient samples revealed a correlation between CSN6 expression and purine and pyrimidine metabolism. A colitis-associated colorectal cancer model established that Csn6 intestinal conditional deletion decreased tumor development and altered nucleotide metabolism. CSN6 knockdown increased the chemosensitivity of colorectal cancer cells in vitro and in vivo, which could be partially reversed with nucleoside supplementation. Isotope metabolite tracing showed that CSN6 loss reduced de novo nucleotide synthesis. Mechanistically, CSN6 upregulated purine and pyrimidine biosynthesis by increasing expression of PHGDH, a key enzyme in the serine synthesis pathway. CSN6 inhibited β-Trcp–mediated DDX5 polyubiquitination and degradation, which in turn promoted DDX5-mediated PHGDH mRNA stabilization, leading to metabolic reprogramming and colorectal cancer progression. Butyrate treatment decreased CSN6 expression and improved chemotherapy efficacy. These findings unravel the oncogenic role of CSN6 in regulating nucleotide metabolism and chemosensitivity in colorectal cancer. Significance: CSN6 deficiency inhibits colorectal cancer development and chemoresistance by downregulating PHGDH to block nucleotide biosynthesis, providing potential therapeutic targets to improve colorectal cancer treatment.
LepRb+ cell–specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice
Authors: Min-Hyun Kim, Yuan Li, Qiantao Zheng, Lin Jiang, Martin G. Myers, Wen-Shu Wu, Liangyou Rui
Journal: Journal of Clinical Investigation (2022)

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug — also known as Snai2 — recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell–specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron–specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.
Long-Chain Acylcarnitines Induce Senescence of Invariant Natural Killer T Cells in Hepatocellular Carcinoma
Authors: Xue Cheng, Xiaosheng Tan, Wei Wang, Ziyao Zhang, Rongfei Zhu, Mi Wu, Mingyu Li, Yiqing Chen, Zhihui Liang, Peng Zhu, Xiongwen Wu, Xiufang Weng
Journal: Cancer Research (2022)

Abstract CD1d-restricted invariant natural killer T (iNKT) cells actively patrol the liver and possess valuable antitumor potential. However, clinical trials evaluating administration of iNKT cell–specific agonist α-galactosylceramide (α-GalCer) have failed to achieve obvious tumor regression. Improving the efficacy of iNKT cell–based immunotherapy requires a better understanding of the factors restraining the clinical benefits. In the context of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we found circulating and hepatic iNKT cells were hyperactivated but demonstrated imbalances in ratio and defective α-GalCer responsiveness. Exogenous IL2 helped to expand residual α-GalCer–responsive clones with reduced T-cell receptor diversity. However, transcriptome-wide analysis revealed activation of the senescence-associated secretory phenotype and dampened cytotoxicity in iNKT cells, weakening their immune surveillance capacity. The senescent status of iNKT cells from the patients was further illustrated by cell-cycle arrest, impaired telomere maintenance, perturbed calcium transport-related biological processes, and altered metabolism. Lipidomic profiling revealed the accumulation of long-chain acylcarnitines (LCAC) and aberrant lipid metabolism in HCC tissue. Exogenous LCACs, especially palmitoyl-carnitine and stearoyl-carnitine, inhibited iNKT cell expansion and promoted senescence. Collectively, our results provide deeper insights into iNKT cell dysregulation and identify a cell senescence–associated challenge for iNKT cell–based immunotherapy in HBV-related HCC. The mechanistic links between iNKT cell senescence and accumulated LCACs suggest new targets for anti-HCC immunotherapies. Significance: Patients with HBV-related HCC exhibit a cell senescence–associated dysregulation of invariant natural killer cells that is related to altered lipid metabolism and accumulated LCACs in tumor tissue.
<scp>PKCα</scp> interacts with Ca<sub>v</sub>1.3 calcium channels to promote the Ca<sub>v</sub>1.2/Ca<sub>v</sub>1.3 duo tuning Th2 functions
Authors: Nicolas Giang, Thomas Villeneuve, Kilian Maire, José Enrique Mejia, Jean‐Charles Guéry, Lucette Pelletier, Magali Savignac
Journal: Allergy (2022)
Cancer epigenetics in clinical practice
Authors: Veronica Davalos, Manel Esteller
Journal: CA A Cancer Journal for Clinicians (2022)

Abstract Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer‐specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation‐based assays and epigenetic drugs already approved by the US Food and Drug Administration.
Functional Skeletal Muscle Regeneration Using Muscle Mimetic Tissue Fabricated by Microvalve‐Assisted Coaxial 3D Bioprinting
Authors: Hanna Lee, Soon Hee Kim, Ji Seung Lee, Young Jin Lee, Ok Joo Lee, Olatunji Ajiteru, Md Tipu Sultan, Suk Woo Lee, Chan Hum Park
Journal: Advanced Healthcare Materials (2022)

Abstract 3D‐printed artificial skeletal muscle, which mimics the structural and functional characteristics of native skeletal muscle, is a promising treatment method for muscle reconstruction. Although various fabrication techniques for skeletal muscle using 3D bio‐printers are studied, it is still challenging to build a functional muscle structure. A strategy using microvalve‐assisted coaxial 3D bioprinting in consideration of functional skeletal muscle fabrication is reported. The unit (artificial muscle fascicle: AMF) of muscle mimetic tissue is composed of a core filled with medium‐based C2C12 myoblast aggregates as a role of muscle fibers and a photo cross‐linkable hydrogel‐based shell as a role of connective tissue in muscles that enhances printability and cell adhesion and proliferation. Especially, a microvalve system is applied for the core part with even cell distribution and strong cell–cell interaction. This system enhances myotube formation and consequently shows spontaneous contraction. A multi‐printed AMF (artificial muscle tissue: AMT) as a piece of muscle is implanted into the anterior tibia (TA) muscle defect site of immunocompromised rats. As a result, the TA‐implanted AMT responds to electrical stimulation and represents histologically regenerated muscle tissue. This microvalve‐assisted coaxial 3D bioprinting shows a significant step forward to mimicking native skeletal muscle tissue.
RNA Therapeutics for Improving CAR T-cell Safety and Efficacy
Authors: Philipp Schaible, Wolfgang Bethge, Claudia Lengerke, Reka Agnes Haraszti
Journal: Cancer Research (2022)

Abstract Autologous chimeric antigen receptor (CAR) T cells have recently emerged as potent tools in the fight against cancer, with promising therapeutic efficacy against hematological malignancies. However, several limitations hamper their widespread clinical use, including availability of target antigen, severe toxic effects, primary and secondary resistance, heterogeneous quality of autologous T cells, variable persistence, and low activity against solid tumors. Development of allogeneic off-the-shelf CAR T cells could help address some of these limitations but is impeded by alloimmunity with either rejection and limited expansion of allo-CAR T cells or CAR T cells versus host reactions. RNA therapeutics, such as small interfering RNAs, microRNAs, and antisense oligonucleotides, are able to silence transcripts in a sequence-specific and proliferation-sensitive way, which may offer a way to overcome some of the challenges facing CAR T-cell development and clinical utility. Here, we review how different RNA therapeutics or a combination of RNA therapeutics and genetic engineering could be harnessed to improve the safety and efficacy of autologous and allogeneic CAR T-cell therapy.
Deregulation of SPOP in Cancer
Authors: Hui Zhang, Xiaofeng Jin, Haojie Huang
Journal: Cancer Research (2022)

Abstract Speckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex. SPOP is frequently mutated in prostate and endometrial cancers, whereas it is overexpressed in renal cell carcinoma (RCC). SPOP can mediate both degradable and nondegradable polyubiquitination of a number of substrates with diverse biological functions such as androgen receptor (AR), SRC-3, TRIM24, BRD4, PD-L1, 53BP1, GLP/G9a, c-Myc, SENP7, among others. Cancer-associated SPOP mutants often impair SPOP binding and polyubiquitination of its substrates to influence various cancer-relevant pathways, which include androgen/AR signaling, DNA repair and methylation, cellular stress surveillance, cancer metabolism, and immunity. Although SPOP is recognized as a tumor suppressor in prostate and endometrial cancers, it acts like an oncoprotein in RCC. This review provides an overview of the recent progress in understanding of the upstream regulators of SPOP and its downstream targets, highlights the significant impact of SPOP mutations and overexpression on cancer pathogenesis, and discusses the potential of targeting SPOP for cancer treatment.
PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
Authors: Li-Li Long, Si-Cong Ma, Ze-Qin Guo, Yan-Pei Zhang, Zhenzhen Fan, Li-Juan Liu, Li Liu, Duan-Duan Han, Meng-Xin Leng, Jian Wang, Xue-Jun Guo, Jia-Le Tan, Xiao-Ting Cai, Yan Lin, Xinghua Pan, De-Hua Wu, Xue Bai, Zhong-Yi Dong
Journal: Cancer Research (2022)

Abstract Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. Significance: Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.
Monkeypox in Montréal: Epidemiology, Phylogenomics, and Public Health Response to a Large North American Outbreak
Authors: Luke B. Harrison, Geneviève Bergeron, Geneviève Cadieux, Hugues Charest, Judith Fafard, Inès Levade, Antoine Cloutier Blais, Emmanuelle Huchet, Benoît Trottier, Dragos Vlad, Jason Szabo, Réjean Thomas, Sébastien Poulin, Christina Greenaway, Gerasimos J. Zaharatos, Matthew Oughton, Arpita Chakravarti, Robert Pilarski, Andrew Bui-Nguyen, Khadija Benomar, Michael D. Libman, Donald C. Vinh, Ana T. Duggan, Morag Graham, Marina B. Klein, Sapha Barkati
Journal: Annals of Internal Medicine (2022)

Monkeypox, a viral zoonotic disease, is causing a global outbreak outside of endemic areas.To characterize the outbreak of monkeypox in Montréal, the first large outbreak in North America.Epidemiologic and laboratory surveillance data and a phylogenomic analysis were used to describe and place the outbreak in a global context.Montréal, Canada.Probable or confirmed cases of monkeypox.Epidemiologic, clinical, and demographic data were aggregated. Whole-genome sequencing and phylogenetic analysis were performed for a set of outbreak sequences. The public health response and its evolution are described.Up to 18 October 2022, a total of 402 cases of monkeypox were reported mostly among men who have sex with men (MSM), most of which were suspected to be acquired through sexual contact. All monkeypox genomes nested within the B.1 lineage. Montréal Public Health worked closely with the affected communities to control the outbreak, becoming the first jurisdiction to offer 1 dose of the Modified Vaccinia Ankara-Bavarian Nordic vaccine as preexposure prophylaxis (PrEP) to those at risk in early June 2022. Two peaks of cases were seen in early June and July (43 and 44 cases per week, respectively) followed by a decline toward near resolution of the outbreak in October. Reasons for the biphasic peak are not fully elucidated but may represent the tempo of vaccination and/or several factors related to transmission dynamics and case ascertainment.Clinical data are self-reported. Limited divergence among sequences limited genomic epidemiologic conclusions.A large outbreak of monkeypox occurred in Montréal, primarily among MSM. Successful control of the outbreak rested on early and sustained engagement with the affected communities and rapid offer of PrEP vaccination to at-risk persons.None.
Correction: Biallelic <i>PAX5</i> mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder
Authors: Fabian M.P. Kaiser, Sarah Gruenbacher, Maria Roa Oyaga, Enzo Nio, Markus Jaritz, Qiong Sun, Wietske van der Zwaag, Emanuel Kreidl, Lydia M. Zopf, Virgil A.S.H. Dalm, Johan Pel, Carolin Gaiser, Rick van der Vliet, Lucas Wahl, André Rietman, Louisa Hill, Ines Leca, Gertjan Driessen, Charlie Laffeber, Alice Brooks, Peter D. Katsikis, Joyce H.G. Lebbink, Kikuë Tachibana, Mirjam van der Burg, Chris I. De Zeeuw, Aleksandra Badura, Meinrad Busslinger
Journal: The Journal of Experimental Medicine (2022)

The authors regret that in the original version of Fig. 10 C, the Gad1&2, mCherry, and Pax5 smRNA-FISH data of the SN neuron had been accidentally copied from the bottom left row into the bottom right row.The corrected Fig. 10 C is shown here.The contours of the VTA neuron in the bottom right row remain unchanged, and the corrections do not alter the conclusions at the end of the Results section: "smRNA FISH analysis revealed concomitant expression of mCherry and Gad1, Gad2 mRNA in the VTA and SN in cells with and without active Pax5 expression (Fig. 10 C), demonstrating that GABAergic neurons in these regions without active Pax5 expression also originate from Pax5-expressing progenitor cells.
Evaluation of Methods to Detect Shifts in Directional Selection at the Genome Scale
Authors: Louis Duchemin, Vincent Lanore, Philippe Veber, Bastien Boussau
Journal: Molecular Biology and Evolution (2022)

Abstract Identifying the footprints of selection in coding sequences can inform about the importance and function of individual sites. Analyses of the ratio of nonsynonymous to synonymous substitutions (dN/dS) have been widely used to pinpoint changes in the intensity of selection, but cannot distinguish them from changes in the direction of selection, that is, changes in the fitness of specific amino acids at a given position. A few methods that rely on amino-acid profiles to detect changes in directional selection have been designed, but their performances have not been well characterized. In this paper, we investigate the performance of six of these methods. We evaluate them on simulations along empirical phylogenies in which transition events have been annotated and compare their ability to detect sites that have undergone changes in the direction or intensity of selection to that of a widely used dN/dS approach, codeml’s branch-site model A. We show that all methods have reduced performance in the presence of biased gene conversion but not CpG hypermutability. The best profile method, Pelican, a new implementation of Tamuri AU, Hay AJ, Goldstein RA. (2009. Identifying changes in selective constraints: host shifts in influenza. PLoS Comput Biol. 5(11):e1000564), performs as well as codeml in a range of conditions except for detecting relaxations of selection, and performs better when tree length increases, or in the presence of persistent positive selection. It is fast, enabling genome-scale searches for site-wise changes in the direction of selection associated with phenotypic changes.
Effectiveness of BNT162b2 COVID-19 vaccination in prevention of hospitalisations and severe disease in adults with SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant between June 2021 and July 2022: a prospective test negative case–control study
Authors: Anastasia Chatzilena, Catherine Hyams, Rob Challen, Robin Marlow, Jade King, David Adegbite, Jane Kinney, Madeleine Clout, Nick Maskell, Jennifer Oliver, Leon Danon, Adam Finn, Anna Morley, Amelia Langdon, Anabella Turner, Anya Mattocks, Bethany Osborne, Charli Grimes, Claire Mitchell, Emma Bridgeman, Emma Scott, Fiona Perkins, Francesca Bayley, Gabriella Ruffino, Gabriella Valentine, Grace Tilzey, Johanna Kellett Wright, Julia Brzezinska, Julie Cloake, Katarina Milutinovic, Kate Helliker, Katie Maughan, Kazminder Fox, Konstantina Minou, Lana Ward, Leah Fleming, Leigh Morrison, Lily Smart, Louise Wright, Lucy Grimwood, Maddalena Bellavia, Marianne Vasquez, Maria Garcia Gonzalez, Milo Jeenes-Flanagan, Natalie Chang, Niall Grace, Nicola Manning, Oliver Griffiths, Pip Croxford, Peter Sequenza, Rajeka Lazarus, Rhian Walters, Robin Marlow, Robyn Heath, Rupert Antico, Sandi Nammuni Arachchge, Seevakumar Suppiah, Taslima Mona, Tawassal Riaz, Vicki Mackay, Zandile Maseko, Zoe Taylor, Zsolt Friedrich, Zsuzsa Szasz-Benczur
Journal: The Lancet Regional Health - Europe (2022)

Whilst other studies have reported the effectiveness of mRNA vaccination against hospitalisation, including emergency department or intensive care admission, few have assessed effectiveness against other more clinically robust indices of COVID-19 severity.